[Statement of the Austrian Society of Pneumology (ASP)]. / Stellungnahme der Österreichischen Gesellschaft für Pneumologie (ÖGP): Management von Patienten mit SARS-CoV-2-Infektionen und von Patienten mit chronischen Lungenerkrankungen während der COVID-19-Pandemie (Stand 27.04.2020).

The COVID-19 pandemic is currently a challenge worldwide. In Austria, a crisis within the health care system has so far been avoided. The treatment of patients with community-acquired pneumonia (CAP), including SARS-CoV­2 infections, should continue to be based on evidence-based CAP guidelines during the pandemic. However, COVID-19-specific adjustments are useful. The treatment of patients with chronic lung diseases must be adapted during the pandemic, but must still be guaranteed.

Pulmonary and cardiac drugs: clinically relevant interactions.

Chronic heart and lung diseases are very common in the elderly population. The combination of chronic heart failure and chronic obstructive pulmonary disease (COPD) is also common and, according to current guidelines, these patients should be treated for both diseases. In patients with heart failure, beta-blockers are very important drugs because their use is associated with significantly improved morbidity and mortality. These beneficial effects were documented in patients with and without COPD, although theoretically there is a risk for bronchoconstriction, particularly with non-beta1 selective blockers. In COPD patients, long-acting sympathomimetics (LABA) improve lung function, dyspnea, and quality of life and their combination with a beta-blocker makes sense from a pharmacological and a clinical point of view, because any potential arrhythmogenic effects of the LABA will be ameliorated by the beta-blocker. Inhaled tiotropium, a long-acting muscarinic antagonist (LAMA), has been extensively investigated and no safety concerns were reported in terms of cardiac adverse effects. The same applies for the other approved LAMA preparations and LAMA-LABA combinations. Severe COPD causes air-trapping with increasing pressures in the thorax, leading to limitations in blood return into the thorax from the periphery of the body. This causes a decrease in stroke volume and cardiac index and is associated with dyspnea. All these adverse effects can be ameliorated by potent anti-obstructive therapy as recently shown by means of a LABA-LAMA combination.

[Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Lungenkrankheiten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

[Research in Austria - the Ludwig Boltzmann Institute for Lung Vascular Research]. / Forschung in Österreich - das Ludwig Boltzmann Institut für Lungengefäßforschung.

The Ludwig Boltzmann Institute for Lung Vascular Research was founded in 2010 and performs basic and clinical research on the field of chronic pulmonary vascular diseases. The major projects of the institute focus on the investigation of the pathomechanisms of pulmonary vascular remodeling, the development of novel non-invasive diagnostic techniques of pulmonary hypertension and the early detection of pulmonary vascular diseases. The institute closely cooperates with patient organizations and aims to contribute to the development of improved diagnostic and therapeutic approaches for patients with pulmonary vascular diseases. In this short overview the most important results of the first six years of the institute will be summarized.

[Pulmonary (Arterial) Hypertension]. / Pulmonal (arterielle) Hypertonie.

Pulmonary arterial hypertension (PAH) is a rare disease characterised by vascular remodelling of the small lung arteries leading to a decrease of the vessel lumen and eventually to occlusion. According to the current guidelines, PAH is defined by a pulmonary arterial pressure ≥ 25 mmHg, an arterial wedge pressure ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR > 3 WU). The current pathophysiological concepts include disturbances in the production, deposition and composition of the extracellular matrix, inflammatory processes, mutations in the BMPR2 gene as well as mutations in the KCNK3 gene. During the last few years, epigenetic and genetic investigations resulted in new findings which are highly relevant for the diagnosis, prognosis and therapy of PAH. These findings could lead to the development of new, individualised therapy strategies. Currently, several phase I and phase II studies are in progress, in which promising new substances are examined.

[ESC guidelines 2015 on pulmonary hypertension]. / ESC-Leitlinien 2015 zur pulmonalen Hypertonie.

The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines published in 2015 include the most important recommendations for the diagnosis and treatment of pulmonary hypertension (PH). The classification of PH into five groups remained unchanged as compared to the previous recommendations; however, there are minor shifts within the groups. Accordingly, a distinction is made between pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to chronic hypoxia or lung disease, chronic thromboembolic PH and PH due to unclear or multifactorial mechanisms. The diagnosis of PH is based on right heart catheterization where PH is defined as a mean pulmonary arterial pressure ≥ 25 mmHg at rest. For the definition of PAH, in addition to a pulmonary capillary wedge pressure ≤ 15 mmHg, a pulmonary vascular resistance > 3 Wood units is obligatory. Echocardiography is considered to be the most important non-invasive procedure within the diagnostic algorithm and for patients with collagen vascular disease. This is recommended during initial diagnostic work-up and should be followed-up annually. Several novel drugs which were approved since publication of the previous guidelines, were included in the new recommendations. For the first time there is a recommendation for a targeted drug for inoperable chronic thromboembolic PH. An important part of the guidelines is the discussion on PAH upfront combination therapy.

PCK2 activation mediates an adaptive response to glucose depletion in lung cancer.

Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with (13)C3-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from (13)C3-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.

Detection of pulmonary vasculopathy by novel analysis of oxygen uptake in patients with systemic sclerosis: association with pulmonary arterial pressures.

OBJECTIVES: During cardiopulmonary exercise testing (CPET) compromised pulmonary vasculature in patients with systemic sclerosis (SSc) may lead to increases in pulmonary arterial pressures (PAP) and decreased oxygen uptake. We hypothesised that this may lead into a disproportional heart rate (HR) increase with a corresponding V'O2/HR breakpoint and relates to systolic PAP at rest. METHODS: In a prospective design we evaluated V'O2/HR slopes for breakpoints. To understand its physiological meaning, we evaluated V'O2/HR and V'O2/mPAP slopes for breakpoints in a historic data set of SSc patients, in which CPET and right heart catheterisation was performed simultaneously. V'O2/HR slopes with a peak oxygen uptake outside the normal range were defined as pathologic. RESULTS: A breakpoint occurred in both V'O2/mPAP and V'O2/HR slope in 16/34 patients in the historic dataset and occurred in the V'O2/mPAP slope at a lower V'O2in 15 patients. In the prospective dataset, 73/121 patients showed a V'O2/HR breakpoint and achieved a significantly lower peak oxygen uptake compared to 48/121 patients without a V'O2/HR breakpoint (p=0.036). Mean systolic PAP in 41/121 patients with a pathologic V'O2/HR slope differed significantly from patients without a pathologic V'O2/HR slope (p=0.027). In 27/121 patients with a systolic PAP < 35 mmHg a pathologic V'O2/HR slope was observed. CONCLUSIONS: SSc patients with a V'O2/HR breakpoint are characterised by a decreased oxygen uptake, likely caused by sudden PAP increases during exercise. Importantly, in patients with normal resting SPAP pathologic V'O2/HR slopes were observed. This suggests that these patients are at risk for developing pulmonary hypertension.

[Early diagnosis and therapy in pulmonary hypertension--aspects of a vision]. / Die frühe Diagnose und Therapie der pulmonalen Hypertonie--Aspekte einer Vision.

In patients with pulmonary hypertension progressive vascular changes in the lung precede the clinical and hemodynamic manifestations of the disease. Therefore, early diagnosis and timely treatment of the disease are crucial. This has been the topic of an expert meeting in Greifswald, Germany in June 2012. The current definition of pulmonary hypertension requires a mean pulmonary artery pressure ≥ 25 mmHg at rest, a hemodynamic abnormality already reflecting pulmonary vascular changes beyond early disease. There is increasing evidence supporting the concept that a lower pressure threshold at rest or an abnormal pressure response with exercise better characterize early disease. While right heart catheterization at rest remains the diagnostic gold standard other methods for detecting early disease are explored with echocardiography being the most frequently used technique. Targeted therapy has been approved for patients with pulmonary arterial hypertension (PAH, WHO-group I) in functional class II-IV. Preliminary data in functional class I patients suggest therapeutic potential of theses drugs in early disease as well. Current guidelines propose therapeutic goals based on parameters with prognostic importance. However, these recommendations are based on mostly retrospective analyses of pre-treatment data obtained in patients with pulmonary hypertension in functional class II-IV. Therefore, evidence-based therapeutic goals for early interventions in functional class I patients are lacking.

Pulmonary vascular resistances during exercise in normal subjects: a systematic review.

The physiological range of pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR), and the impact of exercise, age and posture have been a matter of debate for many years. We performed a systematic literature review including all right heart catheterisation data where individual PVR and TPR of healthy subjects both at rest and exercise were available. Data were stratified according to age, exercise level and posture. Supine resting PVR in subjects aged <24 yrs, 24-50 yrs, 51-69 yrs and ≥70 yrs was 61±23, 69±28, 86±15 and 90±39 dyn·s·cm(-5), respectively. Corresponding TPR was 165±50, 164±46, 226±64 and 223±45 dyn·s·cm(-5), respectively. During moderate exercise in subjects aged ≤50 yrs, an 85% increase in cardiac output was associated with a 25% decrease in TPR (p<0.0001) and a 12% decrease in PVR (p<0.01). At 51-69 yrs of age there was no significant decrease in TPR and PVR. In individuals aged ≥70 yrs TPR even increased by 17% (p=0.01), while PVR did not change significantly. At higher exercise levels, TPR decreased in all age groups. In the upright position, based on a limited number of data, resting TPR and PVR were higher than in the supine position and decreased more prominently during exercise, suggesting the release of resting pulmonary vasoconstriction. These data may form a basis to define normal PVR at rest and exercise.

Diagnosis of CTEPH versus IPAH using capillary to end-tidal carbon dioxide gradients.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents an important differential diagnosis to idiopathic pulmonary arterial hypertension (IPAH). We hypothesised that the capillary to end-tidal carbon dioxide gradient at rest and during exercise might help differentiate CTEPH from IPAH. Patients who presented with unequivocal IPAH or CTEPH according to ventilation/perfusion scanning, pulmonary angiography, computed tomography and right heart catheterisation were included in this retrospective study and compared with healthy controls. 21 IPAH patients and 16 CTEPH patients fulfilled the inclusion criteria. Haemodynamics and peak oxygen uptake were comparable, but respiratory rates at rest and during exercise were significantly higher in CTEPH than in IPAH. End-tidal carbon dioxide was significantly lower in CTEPH versus IPAH at rest and during exercise, while capillary carbon dioxide values were similar. Correspondingly, capillary to end-tidal carbon dioxide gradients were significantly increased in CTEPH versus IPAH at rest and during exercise (median (range) 8.6 (3.0-13.7) versus 4.4 (0.9-9.0) (p<0.001) and 9.3 (3.3-13.1) versus 4.1 (0.0-8.8) mmHg (p<0.001), respectively). Although these values were closer to normal in IPAH they were still significantly elevated compared with healthy controls (2.3 (-4.8-8.1) and -1.9 (-5.7-6.2) mmHg, respectively). Capillary to end-tidal carbon dioxide gradients may help to distinguish CTEPH from IPAH based on resting and exercise values.

[Treatment of pulmonary arterial hypertension (PAH): recommendations of the Cologne Consensus Conference 2010]. / Therapie der pulmonal arteriellen Hypertonie (PAH): Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of PAH. This commentary summarizes the results and recommendations of the working group on treatment of PAH.